Many treatments of the vascular system entail the introduction of a device such as a stent, a catheter, a balloon, a wire guide, a cannula, or the like. However, when such a device is introduced into and manipulated through the vascular system, the blood vessel walls can be disturbed or injured. Clot formation or thrombosis often results at the injured site, causing stenosis or occlusion of the blood vessel. Moreover, if the medical device is left within the patient for an extended period of time, thrombus often forms on the device itself, again causing stenosis or occlusion. As a result, the patient is placed at risk of a variety of complications, including heart attack, pulmonary embolism, and stroke. Thus, the use of such a medical device can entail the risk of precisely the problems that its use was intended to ameliorate. Additional complications can arise from these medical procedures. For example, synthetic materials in the blood vessels can also cause platelet aggregation, resulting in some instances in potentially life-threatening thrombus formation.
Nitric oxide has recently been shown to dramatically reduce thrombocyte and fibrin aggregation/adhesion and smooth muscle cell hyperplasia while promoting endothelial cell growth (Cha et al., “Effects of Endothelial Cells and Mononuclear Leukocytes on Platelet Aggregation,” Haematologia (Budap), 30(2): 97-106 (2000); Lowson et al., “The Effect of Nitric Oxide on Platelets When Delivered to the Cardiopulmonary Bypass Circuit,” Anesth. Analg., 89(6): 1360-1365 (1999); Riddel et al., “Nitric Oxide and Platelet Aggregation,” Vitam. Horm., 57: 25-48 (1999); Gries et al., “Inhaled Nitric Oxide Inhibits Human Platelet Aggregation, P-selectin expression, and Fibrinogen Binding In Vitro and In Vivo,” Circulation, 97(15): 1481-1487 (1998); and Lüscher, “Thrombocyte-vascular Wall Interaction and Coronary Heart Disease,” Schweiz Med. Wochenschr., 121(51-52): 1913-1922 (1991)).
In addition to its role in promoting angiogenesis and inhibiting thrombosis, NO has been implicated in a variety of bioregulatory processes, including normal physiological control of blood pressure, neurotransmission, cancer, and infectious diseases. See, e.g., Moncada, “Nitric Oxide,” J. Hypertens. Suppl., 12(10): S35-39 (1994); Moncada et al., “Nitric Oxide from L-Arginine: A Bioregulatory System,” Excerpta Medica, International Congress Series 897 (Elsevier Science Publishers B. V.: Amsterdam, 1990); Marletta et al., “Unraveling the Biological Significance of Nitric Oxide,” Biofactors 2: 219-225 (1990); Ignarro, “Nitric Oxide. A Novel Signal Transduction Mechanism for Transcellular Communication,” Hypertension, 16: 477-483 (1990); Hariawala et al., “Angiogenesis and the Heart: Therapeutic Implications,” J. R. Soc. Med., 90(6): 307-311 (1997); Granger et al., “Molecular and Cellular Basis of Myocardial Angiogenesis,” Cell. Mol. Biol. Res., 40(2): 81-85 (1994); Chiueh, “Neuroprotective Properties of Nitric Oxide,” Ann. N.Y. Acad. Sci., 890: 301-311 (1999); Wink et al., “The Role of Nitric Oxide Chemistry in Cancer Treatment,” Biochemistry (Moscow), 63(7): 802-807 (1998); Fang, F. C., “Perspectives Series: Host/Pathogen Interactions. Mechanisms of Nitric Oxide-Antimicrobial Activity,” J. Clin. Invest., 99(12): 2818-25 (1997); and Fang, F. C., “Nitric Oxide and Infection,” (Kluwer Academic/Plenum Publishers: New York, 1999).
One approach for treating a biological disorder associated with the implantation of a medical device involves prophylactically supplying the injury site with therapeutic levels of NO. This can be accomplished by stimulating the endogenous production of NO or using exogenous NO sources. Methods to regulate endogenous NO release have primarily focused on activation of enzymatic pathways with excess NO metabolic precursors like L-arginine and/or increasing the local expression of nitric oxide synthase (NOS) using gene therapy. U.S. Pat. Nos. 5,945,452, 5,891,459, and 5,428,070 describe the sustained NO elevation using orally administrated L-arginine and/or L-lysine while U.S. Pat. Nos. 5,268,465, 5,468,630, and 5,658,565 describe various gene therapy approaches. Other various gene therapy approaches have been described in the literature. See, e.g., Smith et al., “Gene Therapy for Restenosis,” Curr. Cardiol. Rep., 2(1): 13-23 (2000); Alexander et al., “Gene Transfer of Endothelial Nitric Oxide Synthase but not Cu/Zn Superoxide Dismutase restores Nitric Oxide Availability in the SHRSP,” Cardiovasc. Res., 47(3): 609-617 (2000); Channon et al., “Nitric Oxide Synthase in Atherosclerosis and Vascular Injury: Insights from Experimental Gene Therapy,” Arterioscler. Thromb. Vasc. Biol., 20(8): 1873-1881 (2000); Tanner et al., “Nitric Oxide Modulates Expression of Cell Cycle Regulatory Proteins: A Cytostatic Strategy for Inhibition of Human Vascular Smooth Muscle Cell Proliferation,” Circulation, 101(16): 1982-1989 (2000); Kibbe et al., “Nitric Oxide Synthase Gene Therapy in Vascular Pathology,” Semin. Perinatol., 24(1): 51-54 (2000); Kibbe et al., “Inducible Nitric Oxide Synthase and Vascular Injury,” Cardiovasc. Res., 43(3): 650-657 (1999); Kibbe et al., “Nitric Oxide Synthase Gene Transfer to the Vessel Wall,” Curr. Opin. Nephrol. Hypertens., 8(1): 75-81 (1999); Vassalli et al., “Gene Therapy for Arterial Thrombosis,” Cardiovasc. Res., 35(3): 459-469 (1997); and Yla-Herttuala, “Vascular Gene Transfer,” Curr. Opin. Lipidol., 8(2): 72-76 (1997). In the case of preventing restenosis, however, these methods have not proved clinically effective. Similarly, regulating endogenously expressed NO using gene therapy techniques such as NOS vectors remains highly experimental. Also, there remain significant technical hurdles and safety concerns that must be overcome before site-specific NOS gene delivery will become a viable treatment modality.
The exogenous administration of gaseous nitric oxide is not feasible due to the highly toxic, short-lived, and relatively insoluble nature of NO in physiological buffers. As a result, the clinical use of gaseous NO is largely restricted to the treatment of neonates with conditions such as persistent pulmonary hypertension (Weinberger et al., “The Toxicology of Inhaled Nitric Oxide,” Toxicol. Sci., 59(1): 5-16 (2001); Kinsella et al., “Inhaled Nitric Oxide: Current and Future Uses in Neonates,” Semin. Perinatol., 24(6): 387-395 (2000); and Markewitz et al., “Inhaled Nitric Oxide in Adults with the Acute Respiratory Distress Syndrome,” Respir. Med., 94(11): 1023-1028 (2000)). Alternatively, however, the systemic delivery of exogenous NO with such prodrugs as nitroglycerin has long enjoyed widespread use in the medical management of angina pectoris or the “chest pain” associated with atherosclerotically narrowed coronary arteries. There are problems with the use of agents such as nitroglycerin. Because nitroglycerin requires a variety of enzymes and cofactors in order to release NO, repeated use of this agent over short intervals produces a diminishing therapeutic benefit. This phenomenon is called drug tolerance and results from the near or complete depletion of the enzymes/cofactors needed in the blood to efficiently convert nitroglycerin to a NO-releasing species. By contrast, if too much nitroglycerin is initially given to the patient, it can have devastating side effects including severe hypotension and free radical cell damage.
One potential method for overcoming the disadvantages associated with NO prodrug administration is to provide NO-releasing therapeutics that do not require activation by endogenous enzyme systems. Early efforts to provide NO-releasing compounds suitable for in vivo use were described in U.S. Pat. No. 4,954,526.
Diazeniumdiolates comprise a diverse class of NO-releasing compounds/materials that are known to exhibit sufficient stability to be useful as therapeutics. Although discovered more than 100 years ago by Traube et al. (Liebigs Ann. Chem., 300: 81-128 (1898)), the chemistry and properties of diazeniumdiolates have been extensively reinvestigated by Keefer and co-workers, as described in U.S. Pat. Nos. 6,750,254, 6,703,046, 6,673,338, 6,610,660, 6,511,991, 6,379,660, 6,290,981, 6,270,779, 6,232,336, 6,200,558, 6,110,453, 5,910,316, 5,814,666, 5,814,565, 5,731,305, 5,721,365, 5,718,892, 5,714,511, 5,700,830, 5,691,423, 5,683,668, 5,676,963, 5,650,447, 5,632,981, 5,525,357, 5,405,919, 5,389,675, 5,366,997, 5,250,550, 5,212,204, 5,208,233, 5,185,376, 5,155,137, 5,039,705, and 4,954,526, and in Hrabie et al., J. Org. Chem., 58: 1472-1476 (1993), and incorporated herein by reference.
Diazeniumdiolated compounds have been attached to polymers, substrates, and medical devices. See, for example, U.S. Pat. Nos. 6,703,046, 6,270,779, 6,673,338, 6,200,558, 6,110,453, 5,718,892, 5,691,423, 5,676,963, 5,650,447, 5,632,981, 5,525,357, and 5,405,919.
Thus, despite the extensive literature available on NO and nitric oxide-releasing compounds, there remains a need for stable nitric oxide-releasing polymers that exhibit a sustained release of nitric oxide that can be readily prepared, even from commercially available polymers. Moreover, there exists a need for a medical device, such as a stent, vascular graft, or extracorporeal blood filter, comprised of or coated with a material capable of continuously releasing NO from the first instance of blood contact to days or weeks following its first use. Such a device is useful for treating a biological disorder, such as platelet aggregation, that frequently accompanies the implantation of a medical device.